Researchers identify new mechanism and therapeutic target for neuropathic pain

Neuropathic pain, a condition characterized by abnormal sensitivity to stimuli, can significantly reduce quality of life and is often inadequately managed. According to estimates, neuropathic pain affects 3% to 17% of adults, with around one quarter of individuals with diabetes and one third of individuals with HIV experiencing this type of pain.

In a recent article published in Neuron, researchers reported that a mechanism involving the enzyme Tiam1 in dorsal horn excitatory neurons of the spinal cord is responsible for initiating and maintaining neuropathic pain. They also demonstrated that by targeting Tiam1 in the spinal cord with anti-sense oligonucleotides administered via cerebrospinal fluid injection, it was possible to alleviate hypersensitivity to neuropathic pain effectively.

Lingyong Li, Ph.D., an associate professor at the University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine, stated, “Our study has uncovered a pathophysiological mechanism that triggers, transitions, and maintains neuropathic pain, and we have identified a promising therapeutic target for treating neuropathic pain with long-lasting effects. Understanding the pathophysiology behind neuropathic pain is crucial for developing new and effective therapeutic strategies to treat chronic pain.”

The study was led by Lingyong Li, Ph.D., an associate professor at the University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine, and Kimberly Tolias, Ph.D., a professor at Baylor College of Medicine in Houston, Texas.

It has been known that maladaptive changes in neurons of the spinal dorsal horn, including an increase in the size and density of dendritic spines, are a characteristic feature of neuropathic pain. However, the mechanisms responsible for driving this synaptic plasticity have been unclear. Dendrites are branch-like structures attached to the body of a neuron that receive signals from other neurons. The spinal dorsal horn is one of the three gray columns of the spinal cord.

In a related study conducted last year, Li and Tolias discovered that chronic pain in a mouse model caused an activation of Tiam1 in anterior cingulate cortex pyramidal neurons of the brain, leading to an increase in the number of spines on neural dendrites. This higher spine density resulted in an increased number and strength of connections between neurons, a phenomenon known as synaptic plasticity. These increases caused hypersensitivity and were linked to chronic pain-associated depression in the mouse model.

Li and Tolias used mouse models to investigate neuropathic pain caused by nerve injury, chemotherapy, or diabetes. They discovered that Tiam1 is activated in the spinal dorsal horn of mice with neuropathic pain and that knocking out Tiam1 in mice prevented the development of neuropathic pain without causing any apparent abnormalities.

The study revealed that Tiam1 expression in the spinal dorsal horn neurons is crucial for the development of neuropathic pain, but not in the dorsal root ganglion neurons or excitatory forebrain neurons. Moreover, the development of neuropathic pain was found to depend on Tiam1 expression in excitatory neurons rather than inhibitory neurons.

The researchers also determined what Tiam1 does in neuropathic pain. Tiam1 modulates the activity of other proteins involved in building or breaking down the cytoskeletons of cells. The creation of dendritic spines involves the building of cytoskeleton actin filaments. The study showed that Tiam1 is necessary during the development of neuropathic pain to increase the density of dendritic spines on wide dynamic range neurons in the spinal dorsal horn and to enhance synaptic NMDA receptor activity in spinal dorsal horn neurons.

Tiam1 is responsible for activating Rac1, which promotes the polymerization of actin, a protein essential for dendritic spine creation. The researchers discovered that Tiam1-Rac1 signaling is necessary for the initiation, transition, and maintenance of neuropathic pain. To test whether Tiam1 could be a therapeutic target, they injected ASOs into the cerebrospinal fluid of rats to modulate Tiam1 expression. One week after injection, the ASO against Tiam1 decreased protein levels in the spinal dorsal horn by half and significantly reduced neuropathic pain hypersensitivity, an effect that persisted for another two weeks.

Thus, according to Li and Tolias, Tiam1 is a critical mediator of neuropathic pain, coordinating actin cytoskeletal dynamics, dendritic spine morphogenesis, and synaptic receptor function in spinal dorsal horn excitatory neurons in response to nerve damage.

Leave a Comment